Targeting Neuroinflammation in Brain Cancer: Uncovering Mechanisms, Pharmacological Targets, and Neuropharmaceutical Developments

Mahmoud S. Alghamri, Brandon L. McClellan, Margaret S. Hartlage, Santiago Haase, Syed Mohd Faisal, Rohit Thalla, Ali Dabaja, Kaushik Banerjee, Stephen V. Carney, Anzar A. Mujeeb, Michael R. Olin, James J. Moon, Anna Schwendeman, Pedro R. Lowenstein, Maria G. Castro

Research output: Contribution to journalReview articlepeer-review

4 Scopus citations

Abstract

Gliomas are one of the most lethal types of cancers accounting for ∼80% of all central nervous system (CNS) primary malignancies. Among gliomas, glioblastomas (GBM) are the most aggressive, characterized by a median patient survival of fewer than 15 months. Recent molecular characterization studies uncovered the genetic signatures and methylation status of gliomas and correlate these with clinical prognosis. The most relevant molecular characteristics for the new glioma classification are IDH mutation, chromosome 1p/19q deletion, histone mutations, and other genetic parameters such as ATRX loss, TP53, and TERT mutations, as well as DNA methylation levels. Similar to other solid tumors, glioma progression is impacted by the complex interactions between the tumor cells and immune cells within the tumor microenvironment. The immune system’s response to cancer can impact the glioma’s survival, proliferation, and invasiveness. Salient characteristics of gliomas include enhanced vascularization, stimulation of a hypoxic tumor microenvironment, increased oxidative stress, and an immune suppressive milieu. These processes promote the neuro-inflammatory tumor microenvironment which can lead to the loss of blood-brain barrier (BBB) integrity. The consequences of a compromised BBB are deleteriously exposing the brain to potentially harmful concentrations of substances from the peripheral circulation, adversely affecting neuronal signaling, and abnormal immune cell infiltration; all of which can lead to disruption of brain homeostasis. In this review, we first describe the unique features of inflammation in CNS tumors. We then discuss the mechanisms of tumor-initiating neuro-inflammatory microenvironment and its impact on tumor invasion and progression. Finally, we also discuss potential pharmacological interventions that can be used to target neuro-inflammation in gliomas.

Original languageEnglish (US)
Article number680021
JournalFrontiers in Pharmacology
Volume12
DOIs
StatePublished - May 18 2021

Bibliographical note

Funding Information:
This work was supported by the National Institutes of Health/ National Institute of Neurological Disorders andamp; Stroke (NIH/NINDS) Grants R21-NS091555, R37NS094804, and R01NS074387 to MC; R01NS076991, R01NS082311, and R01NS096756 to PL; Rogel Cancer Center Scholar Award and Forbes Senior Research Scholar Award to MC; National institutes of Health/National Institute of Biomedical Imaging and Bioengineering (NIH/NIBIB) Grant R01-EB022563 to JM, PL, and MC; University of Michigan M-Cube; the Department of Neurosurgery; the University of Michigan Rogel Comprehensive Cancer Center; the Pediatric Brain Tumor Foundation (BTF), Leah’s Happy Hearts Foundation, The Chad Tough Foundation (Ian's Friends Foundation (IFF)), and the Biosciences Initiative in Brain Cancer to MC and PL. NIH/NCI T32-CA009676 PostDoctoral Fellowship to MSA.

Publisher Copyright:
© Copyright © 2021 Alghamri, McClellan, Hartlage, Haase, Faisal, Thalla, Dabaja, Banerjee, Carney, Mujeeb, Olin, Moon, Schwendeman, Lowenstein and Castro.

Keywords

  • glioma
  • immunosuppression
  • immunotherapy
  • inflammation
  • tumor microenvironment

PubMed: MeSH publication types

  • Journal Article
  • Review

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